The production of pharmaceuticals is a costly and complex procedure. In general the procedure involves four key stages, namely:                Drug Discovery        Product Development        Process Development for manufacturing the product; and        Manufacture        
Drug discovery involves identifying polymorphs and their salts that may be pharmaceutically active. This involves a high throughput polymorph detection and screening process. Possible pharmaceutical candidates are identified in this screening, and these candidates then progress to the product development stage, where they undergo clinical trials. In the clinical trials one or more active components are combined with certain inert excipients, such as lactose and sucrose. The structure and distribution uniformity of the active ingredient(s) in the combined form is then assessed. For example, the composition is assessed in terms of how it is compressed and bound together in a dosage form. Various excipients can be trialled at this stage until the most suitable excipients are determined. Hence at this stage it is desirable to be able to image the chemical composition. It would be particularly desirable to obtain a three dimensional image in a short period of time and with a high throughput.
The process development stage evaluates how to process the one or more active components with the excipients on the production line. For example, where the active component is being formed into tablets, a suitable process needs to be developed for blending and compressing the components in a tablet press. This is a critical step in pharmaceutical development, as seemingly simple formulations with identical ingredients can perform radically differently depending upon how the ingredients are blended together. For example, it is not uncommon for active ingredients in a dosage form to be unevenly distributed and in clumps, particularly where the dosage concentration is low. This is undesirable, as the therapeutic value of the tablet often depends on the distribution of the active ingredient. This problem is compounded with pharmaceuticals containing highly active ingredients and also with those that are administered by complex delivery systems.
The final phase of the pharmaceutical development procedure is the manufacturing stage. At this stage it is desirable to monitor the composition of the products being manufactured in order maintain quality standards.
Therefore, at all of these stages in the pharmaceutical development process there is a need to be able to obtain information about the composition of a pharmaceutical product. There is also a need to be able to image the pharmaceutical product and obtain a three dimensional image of the composition of the product.
In particular there is a need for three dimensional mapping of pharmaceutical products, particularly highly toxic or reactive ones, in a non-invasive, efficient manner and with minimal contact.
It would also be desirable to have an approach with a high throughput and also to be able to monitor and control the quality of the composition in a short period of time.
Known techniques of assessing pharmaceutical compositions include performing tablet assays, which entail invasive sample preparation procedures such as tablet crushing, dissolution and chromatographic separation of active ingredients from excipients. These techniques are of limited value, however, as all the information on the physical state of the ingredients and how they relate to each other is effectively lost due to their invasive nature. In this regard, the quality of a formulation can be assessed via the structure of the matrix that evolves during the manufacturing process. Therefore it is desirable to have a technique that maintains the matrix structure.
A technique that has been used to assess tablet content uniformity involves staining the sample to generate image contrast between active ingredients and excipients. While this technique maintains the matrix structure, the staining process is invasive.
NIR spectroscopy has been used to image pharmaceuticals, as described in the article entitled “A near infrared view of pharmaceutical formulation analysis” by Lewis, Carroll and Clarke published in NIR News Vol. 12, No. 3 (2001). The technique however, is not able to readily provide an indication of how the active ingredients are heterogeneously distributed throughout the tablet, as only an image of the surface can be obtained.
Another approach uses Raman spectroscopy. This technique obtains Raman image data and applies multi-variant image processing thereto. This can provides a surface map indicating spatial distribution of ingredients. It is generally a better technique than NIR contrast enhancement approaches in that it is able to map active and excipient materials even when both are white powders. However, once again, only an image of the surface of the tablet can be obtained.
Therefore, both NIR and Raman spectroscopy are able to provide images identifying chemical specificity, but due to issues of scattering, they are not able to probe much below the surface of the sample.
Another problem with Raman spectroscopy is that it cannot be used on chemicals that fluoresce, as this masks the Raman signal. Further, high power illumination is a feature of Raman spectroscopy, and this can lead to heating and changes in chemistry of the sample being imaged.
Micro-computed tomography and magnetic resonance imaging are able to provide three-dimensional image information, but these techniques require long periods of time to produce an image.
It is desirable to have a technique that improves testing turnaround time, as this can save large amounts of money through a decrease in the time-to-market.
It is also desirable to provide an improved imaging technique that is able to provide a three dimensional composition representation.